CZ271193A3 - Iodinated aromatic compounds - Google Patents

Abstract

Compounds having the structure <CHEM> wherein (Z &rparstr& COO is the residue of an iodinated aromatic acid; n is an integer from 0 to 6; R<1> and R<2> are independently H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy or aryloxy; R<3> and R<4> are independently H, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, halogen, hydroxy, acylamino, acetamidoalkyl, COO-alkyl and cyano; Q represents the atoms necessary to complete a carbocyclic or heterocyclic unsaturated mono- or bicyclic aromatic ring; and R<5> is H, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, halogen, hydroxy, amino, acylamino, alkoxyalkyl, fluoroalkyl, acetamidoalkyl, COO-alkyl, cyano, carboxamido, sulfonate, sulfonamido, ureido, or carbamyl are useful as contrast agents in x-ray imaging compositions and methods for x-ray diagnostic imaging.

Description

The iodinated aromatic compound i ^r - ⁰

BACKGROUND OF THE INVENTION

The present invention relates to iodinated aromatic compounds which are particularly useful as x-ray contrast agents.

BACKGROUND OF THE INVENTION

X-ray imaging is well known and is an extremely valuable measure for the early detection and diagnosis of various disease states in the human body. The use of contrast agents for image enhancement in medical X-ray imaging procedures is widespread. An excellent summary of iodinated and other contrast agents for medical imaging is reported by D. P. Swanson et al. in Pharmaceuticals in Medical Imaging, MacMillan Publishing Company (1990).

Various iodinated amides and esters which are soluble or insoluble in water are used as contrast agents for X-ray imaging. For example, U.S. Patent No. 3,097,228 discloses 2,4,6-triiodobenzoyloxyalkanoic acid derivatives having the structure represented by the general formula:

COOR ⁴

in which

· R ³ represents hydrogen or lower alkyl,

R is hydrogen or alkanoyl,

R ³ represents a hydrogen atom or an alkanoylamino group and

R ⁴ represents a lower alkyl group.

U.S. Pat. No. 3,144,479 describes iodinated benzoic acid esters of the general formula

COOH

AND

in which

X represents an iodine atom or an amino group and

R is selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, i.e., a group of formula - {CH ₂₎ m wherein R represents an alkyl group, am represents the number 1 or 2, phenyl and a particular iodinated aromatic group.

However, these references do not disclose or suggest compounds that contain an aromatic group linked through an alkylene group to an ester group on an iodinated aromatic ring.

Published European patent application no.

No. 498,482 describes nanoparticular X-ray contrast agents that have been shown to be extremely beneficial for medical imaging. However, particulate contrast agents in certain cases in vivo applications may exhibit less than fully satisfactory enzymatic degradability, for example, in lymphatic fluids, plasma or blood.

It would be desirable to provide compounds useful as X-ray imaging contrast agents having improved enzymatic degradability and / or appropriate solubility profiles.

SUMMARY OF THE INVENTION

Novel iodinated aromatic compounds have been found and produced which are suitable as x-ray contrast agents. The compounds are characterized by an aromatic group linked via an alkylene group to an ester group on an iodinated aromatic ring.

In particular, compounds of the formula I are obtained according to the invention

II (from -H c ~ ο-

(i) wherein (Z) -COO represents a residue of iodinated aromatic acid, n

represents an integer from 0 to 6

Ovodáku, žalkyjlovoíuu, bi ιΛ 'C < ^π ·

R @ 1 and R @ ² independently of one another represent a fluorine, cycloalkyl, aryl, arylalkyl, alkoxy or aryloxy group;

R ² and R ^ are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, halogen, hydroxy, acylamino, acetamidoalkyl, COO-alkyl or CN,

Q represents the atoms necessary to complete the carbocyclic or heterocyclic, unsaturated monocyclic or bicyclic aromatic ring, and

R ⁵ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy or aryloxy, halogen, hydroxy, amino, acylamino, alkoxyalkyl, fluoroalkyl, acetamidoalkyl, COO-alkyl, cyano, sulfonate, sulfonamide, carboxamido a carbamoyl group.

The present invention further relates to an X-ray contrast agent comprising the compound described above.

The method of medical diagnostic imaging caused by X-rays consists in administering the above-described X-ray contrast agent in an amount producing effective contrast to the mammalian body.

An advantageous feature of the invention is that it provides new ones

4a compounds which are particularly useful as x-ray contrast agents.

Another preferred feature of the invention is that it provides compounds having suitable solubility profiles and improved enzymatic degradability.

Preferred embodiments are described below.

In the structure of Formula I above, (Z) -COO is a residue of iodinated aromatic acid. The iodinated aromatic acid may contain one, two, three or more iodine atoms per molecule. Preferred species contain at least two, and more preferably at least three iodine atoms per molecule. The iodinated compounds may contain substituents that do not have a deleterious effect on the compound's ability to enhance the contrast.

Illustrative examples of suitable aromatic acids include:

diatrizoic acid, metrizoic acid, uroconic acid, iothalamic acid, trimesic acid, ioxaglic acid (hexabrix), ioxitalamic acid, tetrajodterephthalic acid, iodipamide and the like.

In preferred embodiments, (Z) -COO is a substituted L iodo-benzoic acid residue such as triiodo-benzoic acid which is substituted with an acyl group, a carbamoyl group and / or an acylamino group.

In the general formula, R @ 1 and R @ ² independently of one another represent a hydrogen atom, a straight or branched alkyl group containing preferably from 1 to 20 carbon atoms, particularly preferably from 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like, a fluoroalkyl group containing from 1 to (2m + 1) fluorine atoms, wherein m is the number of carbon atoms in the alkyl group, the alkyl moiety of which is similar to that described above, such as trifluoromethyl, cycloalkyl, preferably containing from 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, an aryl group, preferably containing from 6 to 10 carbon atoms such as phenyl and naphthyl, an aralkyl group, preferably containing from 7 to 12 carbon atoms, such as is benzyl, an alkoxy group whose alkyl moiety contains from 1 to 20 carbon atoms as described above, or an aryloxy group whose aryl moiety preferably contains from 6 to 10 carbon atoms as described above.

R ³ and R ⁴ are each independently a substituent as defined above for R ¹ and a halogen atom such as chlorine, bromine or iodine, hydroxy, acylamino, i.e. acetamidoalkyl, i.e.

NHCO-alkyl, in which the alkyl moiety is as defined for r 1; above, -COO-alkyl, wherein the alkyl moiety is as defined for R ¹ above, or cyano and the like, wherein R ° and R are independently a substituent as defined for R ³ and R ⁴ above, an alkoxyxalkyl group, wherein the alkyl and alkoxy moieties of this group have the meanings as defined above for R, or R 0 and R ^z together with the nitrogen atom to which they are attached form a four to seven membered saturated or unsaturated nitrogen-containing ring such as piperidinyl, piperizinyl, pyrrolidinyl etc.

However, reactive substituents such as halogen, hydroxy or acylamino are not preferred on the carbon atom attached to the carbocyclic or heterocyclic aromatic ring.

Q represents the atoms necessary to complete the carbocyclic or heterocyclic, unsaturated aromatic radical. The aromatic radical may be a monocyclic or bicyclic group and preferably contains from 5 to 12 ring carbon atoms. The heterocyclic moiety preferably contains one or more sulfur, nitrogen or oxygen atoms as heteroatoms. Examples of preferred carbocyclic aromatic radicals include phenyl and naphthyl. Examples of preferred heterocyclic aromatic radicals include thienyl, furanyl, pyridyl, pyrrolyl, quinolyl, thiazolyl, imidazolyl, pyrimidyl, pyrazinyl and the like. In a particularly preferred embodiment, Q represents the atoms necessary to complete the phenyl moiety.

R is one or more substituents, preferably from 1 to 3, and particularly preferably one substituent selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy or aryloxy as defined for R ¹ above, hereinafter halogen , such as fluorine, chlorine, bromine or iodine, hydroxy, amino, i.e.

K ⁸ /

-N \

Wherein R and R are substituents independently selected from the substituents defined for R ⁶ and R ⁷ above, an acylamino group having an amino moiety as described above, alkoxyalkyl groups wherein the alkyl and alkoxy moieties are as defined for R 6 ¹ above, fluoroalkyl groups as defined for R ¹ above, acetamidoalkyl groups, i.e. groups of the formula

O

II -NH-C-alkyl wherein the alkyl portion is as defined for R ¹ vemezený above,

-COO-alkyl groups wherein the alkyl moiety is as defined for R above, cyano, carboxamido, sulfonate, sulfonamido, ureido or carbamoyl and the like.

The alkyl, cycloalkyl, aryl, aralkyl and alkoxy groups in the substituents R ¹ to R ⁵ of formula I above may be unsubstituted or may be substituted with various substituents that do not adversely affect the stability or efficacy of the compounds as x-ray contrast agents. radiation such as alkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, acyloxy, halogen such as chlorine, bromine and iodine, acylamino, carbalkoxy, alkylcarbonyl, carbamoyl and the like.

The compounds of the present invention can be prepared by contacting a carboxylate derived from an iodinated aromatic acid or a salt thereof, such as a sodium salt, with a functionalized derivative of the general formula

in which it represents a leaving group and

IR, n, Q and R-R have the meanings given above.

Suitable leaving groups include a halogen atom such as bromine, chlorine and iodine, and sulfonyloxy groups such as methanesulfonyloxy and toluenesulfonyloxy carboxylates derived from iodinated aromatic acids and functionalized derivatives used as starting compounds in the preparation of the compounds of this invention are known compounds and or may be prepared by techniques known in the art. For example, suitable functionalized derivatives include those exemplified below. The general reaction scheme is this;

The reaction may be carried out at various temperatures ranging from -78 to 100 ° C, preferably from -40 to 50 ° C, depending primarily on the selected starting compounds. Typically, the reaction may be carried out at room temperature, but heating may facilitate completion of the reaction.

Usually the reaction is carried out at atmospheric pressure, but higher or lower pressures may be contemplated.

The reaction may be carried out in any suitable solvent. Suitable solvents include N, N-dimethylformamide (DMF).

The following are specific illustrative examples of preferred compounds of this invention that have been produced:

- (ethoxycarbonyl) phenyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzoate),

- (2-propoxycarbonyl) phenyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzoate),

4-methoxyphenyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzoate),

4-cyanophenyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzoate),

3,4,5-trimethoxyphenyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzoate), (3,5-diiodo-4-methoxy) phenyl- [3,5-bis (acetylamino) - 2,4,6-triiodo benzoate /,

4-methoxyphenyl- (3-acetylamino-5-acetyl (methyl) amino-2,4,6-triiodo benzoate), benzyl (3,5-bis (acetylamino) -2,4,6-triiodo benzoate) and benzyl -Ν, Ν ¹ -di-n-hexyl- (3,5-bis (acetylamino) -2,4,6-triiodo benzoate).

Preferred compounds of the invention are those of formula I above wherein R ¹ and R ² are hydrogen, Q is phenyl and ⁿ is zero, and are summarized below.

Compound Z

CH3CONH

NHCOCH3

4-CO2C2H5

4-CO ₂ CH (CH ₃ ) 2

4-OCH3

4-CN

3,4,5- (OCH ₃ ) 2,6- (I); 4-OCH3

AND,

CH3COHN

NCOCH ₃ ch ₃

4-OCH 3 (nC ₆ H ₁₃ )

CHiCON

AND

NCOCH 3 - (nC ₆ H ₁₃ )

When used as a contrast agent for X-ray imaging, the compound of the invention preferably contains at least about 35% by weight,

Ó ótiQ »Ί o c · v“ in / - »n A Π S- orxrln

W i “IV i HUtL · VJ ij tri X Vil f J Vt»

In preferred embodiments, the compounds of the invention may be formulated as particulate X-ray contrast agents, preferably nanoparticular X-ray contrast agents, as described in published European Patent Application No. 0 498 482A. Such nanoparticulate compositions can be prepared by dispersing the compounds of this invention in a liquid dispersing medium and wet grinding the compound in the presence of a solid grinding medium and a surface modifier to form nanoparticles. In another embodiment, the surface modifier may be contacted with the compound after attrition.

The X-ray contrast compositions of the present invention comprise the compounds described above, preferably in particulate form, and a physiologically acceptable carrier therefor. For example, the particles may be dispersed in an aqueous liquid that serves as a carrier for the X-ray contrast agent. Other suitable carriers include liquid carriers such as mixed aqueous and non-aqueous solvents, for example water-alcohol mixtures, and suitable non-aqueous solvents, such as alcohols, gels, gases such as air, and powders.

The x-ray contrast agent may contain from about 1 to 99.9% by weight, preferably from 2 to 45% by weight, and particularly preferably from 10 to 25% by weight of the particles of the above-described particles, the remainder of the agent being a carrier, additives and alike. Agents containing up to about 100% by weight of the particles are contemplated when the agent is in lyophilized form.

The dose of the control agent to be administered may be selected according to a technique known to the person skilled in the art such that a sufficiently enhanced contrast effect is obtained. Typical dosages may range from 50 to 350 mg iodine per kilogram body weight of the patient for a variety of imaging applications. For certain uses, for example for lymphography, lower doses, for example from 0.5 to 20 mg of iodine per kilogram, may be effective.

The X-ray imaging contrast agent may comprise one or more conventional additives used to control and / or enhance the X-ray imaging contrast properties. For example, thickeners such as dextran or human serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting agents, mixing agents, other drugs and the like can be used.

Partial listing of certain particular ingredients include gums, sugars such as dextran, human serum albumin, gelatin, sodium alginate, agar, dextin, pectin, and sodium carboxymethylcellulose. Such additives, surfactants, preservatives and the like can be incorporated into the agents of the invention.

Use

The method of diagnostic imaging for use in the medical procedures of the invention consists in introducing into the body of a mammal in need of such X-ray examination, the above-described X-ray contrast agent in an amount providing an effective X-ray contrast. In addition to humans as patients, other mammalian species, such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, cattle, and the like are included in the subjects to be examined. Thereafter, at least a portion of the body containing the administered contrast agent is exposed to X-rays to produce a characteristic X-ray image corresponding to the presence of the contrast agent. The image can then be visualized. For example, a visualization technique for X-rays may be used in a conventional manner, preferably a high contrast technique such as computed tomography.

In another embodiment, the characteristic imaging can be observed directly on a combination of a X-ray sensitive phosphor screen and a silver halide photographic film.

The agents of the invention may be administered by various routes depending on the type of procedure and the anatomical orientation of the tissue to be examined. Suitable routes of administration are intravascular (arterial or venous), gavage, intravenous injection, rectal, subcutaneous, intramuscular, wound, intrathecal, intracisternal, oral, inhalation, directly to the body. cavities such as arthrography and the like.

In addition to preferred applications, for example, for imaging the bloodstream, liver, spleen and lymph nodes, the X-ray contrast agents of the present invention are also unexpectedly useful as contrast agents for any organ or body cavity. For example, the agents of the invention are particularly suitable as angiographic, urographic, myelographic, gastrointestinal, cholecystographic, cholangiographic, arthrographic, hysterosalpingographic, oral and bronchographic contrast media.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be illustrated by the following examples, which are in no way intended to limit the invention.

Example 1

Process for preparing 4-methoxyphenyl- (3,5-bis (acetylamino) -2,4,6-triiodo benzoate) - compound 3

To a stirred solution of 25 g (39 mmol) of diatrizoic acid sodium salt in 200 ml of dimethylformamide was added 5.8 ml (42 mmol) of 4-methoxybenzyl chloride over 30 minutes. The resulting mixture was stirred at room temperature overnight. A further 1 ml of 4-methoxybenzyl chloride was added and the mixture was stirred for 24 hours. The solvent was evaporated under reduced pressure to give a white solid residue which was suspended in 300 ml of distilled water. The crude material was collected, washed with water and dried at 70-75 ° C to give a solid, which was then digested with 400 mL of a 1: 1 mixture of chloroform and isopropanol. After cooling, the solid was collected and dried under reduced pressure at 80-85 ° C. This gives 24.3 g of the compound produced as a granular solid, m.p. 244-246 ° C. CI-MS: MH ⁺ 735. ¹ H HMR spectral data (300 MHz) are consistent with the values for the desired substance. Yield 85%.

Analysis for:

calculated: 31.09% C, 2.33% H, 51.86% I, 3.82% N, found: 31.05% C, 2.23% H, 51.84% I, 3.84% N.

Example 2

Process for preparing 4- (ethoxycarbonyl) phenyl (3,5-bis (acetylamino) -2,4,6-triiodobenzoate) - compound 1

(a) Method for the preparation of ethyl 4-bromomethylbenzoate

A mixture of 32.8 g (0.2 mol) of ethyl 4-methylbenzoate, 40 g (0.22 mol) of N-bromosuccinimide and 0.5 g of benzoyl peroxide in 200 ml of carbon tetrachloride is refluxed for 75 minutes. and then evaporated under reduced pressure. The remaining mixture was partitioned between 200 mL of water and 200 mL of dichloromethane.

The organic layer was dried (MgSO 4) and evaporated. This gave 52.6 g of a pale yellow oil. The oil was dissolved in 200 mL hexane, filtered and dried over magnesium sulfate. The filtrate was evaporated under reduced pressure to give 49.2 g of crude material as a pale yellow oil, which was used in the next step without purification. Yield 100%. ¹ H NMR spectral data (300 MHz) are consistent with the values for the desired substance which contains about 10% unreacted benzoic ester.

b) Process for preparing 4- (ethoxycarbonyl) phenyl- [3,5-bis (acetylamino) -2,4,6-triiodobenzoate]

A mixture of 25 g (39 mmol) of diatrizoic acid sodium salt and 12.2 g (50 mmol) of crude ethyl (4-bromomethylbenzoate) described above in 200 ml of dimethylformamide is stirred at room temperature for 6 hours and then evaporated to dryness. under reduced pressure after allowing the reaction mixture to stand overnight. The residue is suspended in 300 ml of water and the resulting insoluble solid is collected, washed with water and air-dried. The crude material is digested with 300 ml of ethanol, collected and dried under reduced pressure at 105-110 ° C,

27.6 g of analytically pure compound are obtained, m.p. 234 DEG-236 DEG C. (dec.). CI-MS: MH ⁺ 777. ² H NMR spectral data (300 MHz) are consistent with

required substance. Yield 91 % theory Analysis for ^C 21 ^H 19 Jan ₃ N ₂ ° ₆ : calculated: 32.50 % C, 2.47% H, 3.61 % N, found: 32.73 % C, 2.35% H, 3.41 % N.

Examples 3 to 7

In a similar manner to that described in Examples 1 and 2 above, the synthesis leading to the following compounds was performed:

4- (2-propoxycarbonyl) phenyl- [3,5-bis (acetylamino) -2,4,6-triiodobenzoate],

4-cyanophenyl- (3,5-bis (acetylamino) -2,4,6-triiodo benzoate),

3,4,5-trimethoxyphenyl- (3,5-bis (acetylamino) -2,4,6-tri iodobenzoate), (3,5-diiodo-4-methoxy) phenyl- [3,5-bis (acetylamino) ) -2,4,6-triiodobenzoate (s)

4-methoxyphenyl- [3-acetylamino-5-acetyl (methyl) amino-2,4,6-triiodobenzoate].

In any case, NMR spectral data (300 MHz), Cl mass spectrum and elemental analysis are consistent with the desired compound.

Example 8

Benzyl (3,5-bis (acetylamino) -2,4,6-triiodobenzoate) was prepared in the same manner as in Example 1 except that benzyl bromide was used in place of 4-methoxybenzyl chloride.

H NMR and C NMR ^J spectral data are consistent with the desired compound.

Example 9

Benzyl (3,5-bis (acetylamino) -2,4,6-triiodo benzoate) was deprotonated with 2.1 equivalents of sodium hydride in dimethylformamide and then treated with 2.1 equivalents of 1-bromohexane. There was thus obtained benzyl N, N ¹ -di-n-hexyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzoate). The HMR and ¹³ C NMR spectral data and the Cl mass spectrum (MH ⁺ = 873) are consistent with the values for the desired compound which is the amide as a mixture of rotating isomers.

Claims (8)

A compound of the general formula o It R ¹ R ^J it I - (Z) - C - O - C - (-) - '| 'n i i R ² R ' ¹ ' wherein (Z) -COO represents a residue of iodinated aromatic acid, n represents an integer from 0 to 6, 1 9 R and R are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy or aryloxy, R ³ and R ⁴ are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, alkoxy or aryloxy, halogen, hydroxy, acylamino, acetamidoalkyl, COO-alkyl or cyano, Q represents the atoms necessary to complete the carbocyclic or heterocyclic, unsaturated monocyclic or bicyclic aromatic ring, and R is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy or aryloxy, halogen, hydroxy, amino, acylamino, alkoxyalkyl, fluoroalkyl, acetamidoalkyl, COO-alkyl 2. acid iodic acid acid acid acid acid group, cyano, carboxamido, sulfonate residue, sulfonamido, ureido or carbamoyl group. A compound according to claim 1 wherein Z- (COO) is an aromatic acid residue selected from diatrizoic, metrizoic, urokonic, iothalamic, trimesic, ioxagalic, ioxitalamic, tetrajodterephthalic and iodipamide. The compound of claim 1, wherein Z- (COO) is a diatrizoic acid residue. The compound of claim 1, wherein Q is the atoms necessary to complete the phenyl ring. A compound according to claim 1, wherein a and R ² are each a hydrogen atom and ⁿ is zero. The compound of claim 1, which is selected from the group consisting of 4- (ethoxycarbonyl) phenyl- [3,5-bis (acetylamino) -2,4,6-tri iodobenzoate], 4- (2-propoxycarbonyl) phenyl- [3,5-bis (acetylamino) -2,4,6-triiodobenzoate], 4-methoxyphenyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzoate), 4-cyanophenyl- (3,5-bis (acetylamino) -2,4,6-triiodobenzene), 3,4,5-trimethoxyphenyl- [3,5-bis (acetylamino) -2,4,6-triiodobenzoate], (3,5-diiodo-4-methoxy) phenyl- [3,5-bis (acetylamino) - 2,4,6-triiodo benzoate /, 4-methoxyphenyl- (3-acetylamino-5-acetyl (methyl) amino-2,4,6-triiodo benzoate), benzyl (3,5-bis (acetylamino) -2,4,6-triiodobenzoate) and benzyl- Ν, Ν'-di-n-hexyl- (3,5-bis (acetylamino) -2,4,6-triiodo benzoate). X-ray contrast composition comprising a compound according to any one of the preceding claims. 8. The X-ray contrast composition of claim 7, further comprising a pharmaceutically acceptable carrier.